DOP023Identification of molecular hallmarks of Inflammatory Bowel Disease presenting with arthropathic comorbidities

Abstract Background Inflammatory arthropathies are frequent extraintestinal manifestations of inflammatory bowel disease (IBD) and share features with rheumatological conditions such as rheumatoid arthritis (RA). Clinical presentation is often ambiguous, as many patients do not meet full criteria for defined arthritic disorders and are thus labelled with clinical descriptions such as arthralgia. This study explores the clinical and molecular relationships between IBD and arthropathic manifestations to identify immune correlates of (inflammatory) joint manifestations of IBD. Methods Between 2010 and 2017, a cross-sectional cohort of 279 patients with IBD, 139 with RA, and 202 healthy controls (HCs) was recruited at the University Hospital Schleswig-Holstein, Campus Kiel. Among IBD patients, 92 presented with arthralgia or clinically diagnosed inflammatory arthropathy (IBDart), while 187 had no musculoskeletal comorbidities (IBDno). Peripheral blood samples collected in PAXGene RNA blood tubes were subjected to RNA sequencing. Differential gene expression (DEG) analysis was adjusted for sex, age group, and remission status. Our analyses compared (1) all disease groups versus HCs and (2) the differentially expressed genes of each disease group to identify unique transcriptional signatures. Results Differential expression analysis identified 291 upregulated and 161 downregulated genes in the IBDart subgroup compared with IBDno. These genes were enriched in pathways related to cell-cell adhesion, Wnt signalling, collagen biosynthesis and lipid metabolism. Notably, a substantial subset of DEGs in IBDart (154 upregulated, 68 downregulated) overlapped with DEGs in the RA group, indicating a molecular signature shared with joint-related inflammatory disease. The overlapping genes were particularly enriched in Wnt signalling, lipid metabolic processes, and DNA modification pathways, biological programs known to be dysregulated in RA. In contrast, type II interferon and interleukin-11 signalling pathways as well as immunoglobulin-mediated immune response were uniquely enriched in the IBDno group. Conclusion These findings suggest that circulating collagen- and tissue repair-related transcriptional programs in IBD-associated arthropathy reflect systemic fibro-inflammatory activity, consistent with patterns described in RA. This molecular pattern was distinct from IBD patients without musculoskeletal manifestations. Integrating molecular profiling with clinical phenotyping may improve the classification and management of patients presenting with IBD-related joint manifestations. References: 1.Riitano G, Spinelli F, Manganelli V, et al. Wnt signaling as a translational target in rheumatoid and psoriatic arthritis. J Transl Med. 2025;23(1):158. Published 2025 Feb 4. doi:10.1186/s12967-025-06174-2 Conflict of interest: Wolff, Christopher Marco: No conflicts. Mishra, Neha: none Kimmig, Franziska: No conflicts P. Bernardes, Joana: I have no conflict of interest to declare Hinrichsen, Finn: Received travel support from Pfizer. Holds shares in 10x Genomics Received research material from CatalYm Guggeis, Martina: No conflicts. Nikolaus, Susanna: No conflict of interest Lieb, Wolfgang: No conflict of interest Franke, Andre: I have no conflicts of interest. Aden, Konrad: Personal Fees: Lecture fee: Takeda, Janssen, Lilly, Abbvie Consulting fee: Takeda, Jannsen, Lilly, Guidepoint Leipe, Jan: research support/clinical trials: Abbott, Boehringer, Pfizer, Gilead, Novartis Scientific advisory board/speakers of bureau: Abbvie, Biogen, BMS, Galapagos, Lilly, medac, MSD, Novartis, Roche, Sanofi, UCB. Schreiber, Stefan Wolfgang: Personal Fees: AbbVie, Alfasigma, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Rosenstiel, Philip: stock ownership Gerion Tran, Florian: No conflict of interest